Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3 × Tg-AD mice
Open accessAbstract
BACKGROUND: Accumulating evidence indicates that Tau pathology can spread from neuron to neuron by intake and coaggregation of the hyperphosphorylated Tau (p-Tau) seeds with the host neuron protein. Thus, clearance of Tau seeds by immunization with Tau antibodies could provide a potential therapeutic opportunity to block the spread of the pathology in Alzheimer's disease (AD) and other tauopathies. We report prevention of the seeding and spread of tau pathology with mouse monoclonal antibody 43D against the N-terminal projection domain of Tau (Tau 6-18) in triple-transgenic AD (3 × Tg-AD) mice. METHODS: Female 11- to 12-month-old 3 × Tg-AD mice were intravenously immunized weekly for 6 weeks with 15 μg/injection of mouse monoclonal antibody 43D or with mouse immunoglobulin G as a control. AD p-Tau isolated from a frozen autopsied AD brain was unilaterally injected into the right hippocampus on the day of the second dose of immunization. Tau pathology and its effect on Aβ pathology were assessed by immunohistochemical staining. RESULTS: We found that the injection of AD p-Tau into the hippocampus of 11- to 12-month-old 3 × Tg-AD mice time-dependently induced Tau aggregation in the hippocampus and promoted the spread of Tau pathology to the contralateral hippocampus. Tau pathology was observed as early as 6 weeks after AD p-Tau injection. Tau pathology templated by AD p-Tau was thioflavin-S-positive and was about two-fold greater than that seen in naive 18-month-old 3 × Tg-AD mice; Tau pathology in the latter was thioflavin-S-negative. Immunization with Tau antibody 43D dramatically blocked AD p-Tau seeding in the ipsilateral hippocampus and inhibited its propagation to the contralateral side in 3 × Tg-AD mice. Furthermore, AD p-Tau injection enhanced the amyloid plaque load in the ipsilateral side, and immunization with 43D showed a tendency to attenuate it. CONCLUSIONS: These findings indicate that AD p-Tau-injected 3 × Tg-AD mice represent a practical model to study the seeding and spread of Tau pathology, their effect on Aβ pathology, and the effect of Tau immunotherapy on both Tau and Aβ pathologies. Immunization with Tau antibody 43D to Tau 6-18 can prevent the seeding and spread of Tau pathology, making it a potential therapeutic treatment for AD and related tauopathies.
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Abnormally hyperphosphorylated or oligomeric tau can be secreted from neurons into the extracellular space, taken up by other normal neurons, and cause interneuronal transfer of tau pathology and spreading of tau toxicity across different brain regions.
“there is a large amount of evidence indicating that the abnormally hyperphosphorylated or oligomeric tau can be secreted from neurons into the extracellular space, then be taken up by other normal neurons, and finally causes interneuronal transfer of tau pathology and spreading of tau toxicity across different brain regions [59–61]”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [61]
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- Authors
- Dai, C.-L., Hu, W., Tung, Y. C., Liu, F., Gong, C.-X., & Iqbal, K.
- Corresponding author
- Iqbal, Khalid
- Venue
- Alzheimer's Research & Therapy
- Published
- 2018-01-31
- Volume
- 10
- Issue
- 1
- Pages
- 13-13
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC5793372
- OpenAlex
- W2795504192
- Cited by
- 99
- References
- 65
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 16 · 2022: 11 · 2021: 11 · 2020: 22 · 2019: 12 · 2018: 11
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Alzheimer s Research & Therapy (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Alzheimer's Association (2015-NIRG-339945, 2016-NIRG-397030)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, hyperphosphorylated tau, tau seeding, tauopathy, passive immunization, tau aggregation, amyloid plaques, tau immunotherapy, thioflavin S, hippocampus
- MeSH terms
- Acyltransferases, Alzheimer Disease, Animals, Antibodies, Monoclonal, Brain, Disease Models, Animal, Female, Humans, Immunoglobulin G, Immunization, Passive, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Random Allocation, tau Proteins, Drosophila Proteins, Presenilin-1, Mice, 129 Strain, Plaque, Amyloid, Administration, Intravenous
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